Henry F. Epstein, M.D.

Cecil H. and Ida Green Distinguished University Chair
Professor and Chair
Department of Neuroscience and Cell Biology
Professor, Departments of Neurology and Biochemistry
M.D., 1968, Stanford University
Postdoctoral, Biochemistry, Stanford University;
Molecular Biophysics and Biochemistry, Yale University;
National Institutes of Health; Medical Research Council Laboratory of Molecular Biology at the University of Cambridge; England

Borden Research Award
NIH Career Development Award
Japanese Society for the Promotion of Science Senior Fellowship
Visiting Professor, University of Basel, BioZentrum, Switzerland
Adjunct Professor, Kwangju Institute of Science and Technology, Korea

The Cytoskeleton in Nerve and Muscle

The current focus of Dr. Epstein's laboratory is on characterizing novel proteins regulating the cytoskeleton. Genetic analysis is now turning to mouse lines as well as Caenorhabditis elegans to facilitate medical applications.

Biochemical and genetic studies on the C. elegans model as well as in various fungal species have demonstrated that a novel molecular chaperone is required for the proper folding, assembly, and function of myosins and myosin-like protein motors. The chaperone protein, named UNC-45 after the canonical gene in C. elegans, binds the well-known molecular chaperone Hsp90 as well as myosin. In mice and humans, two UNC-45-like genes are present and encode closely related but distinct isoforms. One isoform is present in many cell types and appears necessary for cell division and membrane fusion; the other isoform is expressed predominantly in heart and skeletal muscle and is necessry for sarcomere organization. The UNC-45 mammalian homologues may prove to be important targets for genetic and pharmacological intervention in certain cancers and heart failure.

Dr. Epstein's laboratory was part of the international consortium that cloned and identified the myotonic dystrophy locus. The major protein product of that locus, myotonic dystrophy protein kinase (DMPK), is a serine-threonine protein kinase related to Rho kinase and other regulators of cell cycle, cytoskeletal, and membrane-associated processes. DMPK appears to team up with Rho kinase and myosin light chain kinase (MLCK) to regulate the assembly and function of myosin and the actin cytoskeleton. The membrane-associated regulators Rac-1 and Raf-1 activate DMPK whereas the cytosolic RhoA activates Rho kinase. DMPK and negative regulator of cytoskeletal myosin II. Our hypothesis is that DMPK along with MLCK activates the membrane-associated cytoskeleton whereas Rho kinase activates the cytosolic system. The DMPK system may be particularly important in the development and function of highly plastic synapses related to learning and memory of the brain.

Recent Publications

Barral, J.M., Hutagalung, A.H., Brinker, A., Hartl, F.U., and Epstein, H.F. Role for myosin assembly protein UNC-45 as a molecular chaperone for myosin. Science 295:669-671, 2002.
Hutagulung, A.H., Landsverk, M.L., Price, M.G. and Epstein, H.F. The UCS family of myosin chaperones. J. Cell Sci., 115:3983-3990, 2002.
Price, M.G., Landsverk, M.L., Barral, J.M. and Epstein, H. F. Cytoskeletal and sarcomeric roles of two mammalian isoforms of the UNC-45 myosin chaperone. J. Cell Sci., 115:4013-4023, 2002
Schulz, P.E., McIntosh, A.D., Kasten, A.R., Wieringa, B., Rajadarai, H. and Epstein, H.F. A role for myotonic dystrophy protein kinase in synaptic plasticity. J. Neurophysiol. 89:1177-1186, 2003.
Zhang, R. and Epstein, H.F. Homodimerization through coiled-coil regions enhances the activity of the myotonic dystrophy protein kinase. FEBS Lett. 546:281-287, 2003.
Iyer, D., Belaguli, N., Fluck, M., Rowen, B.G., Wei, L., Weigel, N.L., Booth, F.W., Epstein, H.F., Schwartz, R.J. and Balasubramanyam, A. Novel phosphorylation target in the serum response factor MADS box regulates alpha-actin transcription. Biochemistry 42:7477-7486, 2003.
Hoppe, T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister, R. Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-multiubiquitylation complex in C. elegans. Cell, 118:337-349, 2004.
Hoppe, T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister, R. Preview: Myosin assembly: The power of multiubiquitylation. Cell, 118:272-274, 2004.



Henry F. Epstein, M.D. hepstein@utmb.edu Cecil H. and Ida Green Distinguished University Chair Professor and Chair Department of Neuroscience and Cell Biology Professor, Departments of Neurology and Biochemistry M.D., 1968, Stanford University Postdoctoral, Biochemistry, Stanford University; Molecular Biophysics and Biochemistry, Yale University; National Institutes of Health; Medical Research Council Laboratory of Molecular Biology at the University of Cambridge; England Borden Research Award NIH Career Development Award Japanese Society for the Promotion of Science Senior Fellowship Visiting Professor, University of Basel, BioZentrum, Switzerland Adjunct Professor, Kwangju Institute of Science and Technology, Korea The Cytoskeleton in Nerve and Muscle The current focus of Dr. Epstein's laboratory is on characterizing novel proteins regulating the cytoskeleton. Genetic analysis is now turning to mouse lines as well as Caenorhabditis elegans to facilitate medical applications. Biochemical and genetic studies on the C. elegans model as well as in various fungal species have demonstrated that a novel molecular chaperone is required for the proper folding, assembly, and function of myosins and myosin-like protein motors. The chaperone protein, named UNC-45 after the canonical gene in C. elegans, binds the well-known molecular chaperone Hsp90 as well as myosin. In mice and humans, two UNC-45-like genes are present and encode closely related but distinct isoforms. One isoform is present in many cell types and appears necessary for cell division and membrane fusion; the other isoform is expressed predominantly in heart and skeletal muscle and is necessry for sarcomere organization. The UNC-45 mammalian homologues may prove to be important targets for genetic and pharmacological intervention in certain cancers and heart failure. Dr. Epstein's laboratory was part of the international consortium that cloned and identified the myotonic dystrophy locus. The major protein product of that locus, myotonic dystrophy protein kinase (DMPK), is a serine-threonine protein kinase related to Rho kinase and other regulators of cell cycle, cytoskeletal, and membrane-associated processes. DMPK appears to team up with Rho kinase and myosin light chain kinase (MLCK) to regulate the assembly and function of myosin and the actin cytoskeleton. The membrane-associated regulators Rac-1 and Raf-1 activate DMPK whereas the cytosolic RhoA activates Rho kinase. DMPK and negative regulator of cytoskeletal myosin II. Our hypothesis is that DMPK along with MLCK activates the membrane-associated cytoskeleton whereas Rho kinase activates the cytosolic system. The DMPK system may be particularly important in the development and function of highly plastic synapses related to learning and memory of the brain. Recent Publications Barral, J.M., Hutagalung, A.H., Brinker, A., Hartl, F.U., and Epstein, H.F. Role for myosin assembly protein UNC-45 as a molecular chaperone for myosin. Science 295:669-671, 2002. Hutagulung, A.H., Landsverk, M.L., Price, M.G. and Epstein, H.F. The UCS family of myosin chaperones. J. Cell Sci., 115:3983-3990, 2002. Price, M.G., Landsverk, M.L., Barral, J.M. and Epstein, H. F. Cytoskeletal and sarcomeric roles of two mammalian isoforms of the UNC-45 myosin chaperone. J. Cell Sci., 115:4013-4023, 2002 Schulz, P.E., McIntosh, A.D., Kasten, A.R., Wieringa, B., Rajadarai, H. and Epstein, H.F. A role for myotonic dystrophy protein kinase in synaptic plasticity. J. Neurophysiol. 89:1177-1186, 2003. Zhang, R. and Epstein, H.F. Homodimerization through coiled-coil regions enhances the activity of the myotonic dystrophy protein kinase. FEBS Lett. 546:281-287, 2003. Iyer, D., Belaguli, N., Fluck, M., Rowen, B.G., Wei, L., Weigel, N.L., Booth, F.W., Epstein, H.F., Schwartz, R.J. and Balasubramanyam, A. Novel phosphorylation target in the serum response factor MADS box regulates alpha-actin transcription. Biochemistry 42:7477-7486, 2003. Hoppe, T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister, R. Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-multiubiquitylation complex in C. elegans. Cell, 118:337-349, 2004. Hoppe, T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister, R. Preview: Myosin assembly: The power of multiubiquitylation. Cell, 118:272-274, 2004.
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